Table 2.
Predicted pharmacokinetic properties of studied antiretroviral drugs and harpagide 5-O-β-D-glucopyranoside.
| Category | Property (unit) | Inference / Reference Range | |||||
|---|---|---|---|---|---|---|---|
| DTG | LVD | TDF | LCP | HGG | |||
| Absorption | Caco−2 permeability (cm/s) | −4.692 | −5.52 | −5.538 | −5.792 | −6.334 | Optimal: higher than −5.15 or −4.70 |
| MDCK permeability | 1.3e−05 | 1.35e−4 | 1.76e−4 | 2.2e−5 | 4.33e−4 | low permeability: < 2 × 10–6 cm/s medium permeability: 2–20 × 10–6 cm/s high passive permeability: > 20 × 10–6 cm/s |
|
| Pgp-inhibitor | 0.008 | 0.002 | 0.0 | 1.0 | 0.0 | +ve value inhibitor and –ve non inhibitor | |
| Pgp-substrate | 0.053 | 0.003 | 0.146 | 0.001 | 0.971 | +ve value substrate and –ve non substrate | |
| F20 % | 0.097 | 0.769 | 0.116 | 0.004 | 0.995 | +ve value bioavailability < 20 % and –ve value ≥ 20 % | |
| F30 % | 0.084 | 0.24 | 0.891 | 0.002 | 1.0 | +ve value bioavailability < 30 % and –ve value ≥ 30 % | |
| HIA (Human Intestinal Absorption) (%) | 0.008 | 0.064 | 0.002 | 0.082 | 0.549 | +ve value HIA > 30 % and –ve value HIA < 30 % | |
| Distribution | PPB (Plasma protein binding) (%) | 93.66 % | 14.08 | 6.066 % | 101.5 % | 12.23 | Optimal: < 90 %. |
| Fu | 2.840 % | 80.84 | 78.70 % | 0.807 % | 56.21 | Low: <5 %; Middle: 5–20 %; High: > 20 % | |
| VD | 1.089 | 0.823 | 0.918 | 0.643 | 0.216 | Optimal: 0.04–20 L/kg | |
| BBB (Blood brain barrier) (%) | 0.293 | 0.636 | 0.171 | 0.156 | 0.35 | +ve value BBB positive and –ve value BBB negative. | |
| Metabolism | CYP1A2-inhibitor | 0.034 | 0.028 | 0.033 | 0.063 | 0.0 | >0.5: An inhibitor |
| CYP1A2-substrate | 0.135 | 0.778 | 0.129 | 0.556 | 0.034 | >0.5: Substrate | |
| CYP2C19-inhibitor | 0.245 | 0.069 | 0.096 | 0.597 | 0.002 | >0.5: An inhibitor | |
| CYP2C19-substrate | 0.168 | 0.077 | 0.053 | 0.18 | 0.087 | >0.5: Substrate | |
| CYP2C9-inhibitor | 0.452 | 0.006 | 0.048 | 0.961 | 0.0 | >0.5: An inhibitor | |
| CYP2C9-substrate | 0.89 | 0.156 | 0.045 | 0.932 | 0.063 | >0.5: Substrate | |
| CYP2D6-inhibitor | 0.027 | 0.011 | 0.062 | 0.624 | 0.0 | >0.5: An inhibitor | |
| CYP2D6-substrate | 0.197 | 0.25 | 0.036 | 0.137 | 0.072 | >0.5: Substrate | |
| CYP3A4-inhibitor | 0.079 | 0.006 | 0.316 | 0.982 | 0.011 | >0.5: An inhibitor | |
| CYP3A4-substrate | 0.119 | 0.095 | 0.289 | 0.934 | 0.002 | >0.5: Substrate | |
| Excretion | Clearance (mL/min/kg) | 2.721 | 4.71 | 5.251 | 5.458 | 0.951 | High: >15 mL/min/kg; moderate: 5–15 mL/min/kg; low: <5 mL/min/kg |
| T1/2 (Half life) (H) | 0.109 | 0.858 | 0.897 | 0.001 | 0.449 | long half-life: >3 h; short half-life: <3 h | |
| Toxicity | hERG (hERG blockers) | 0.031 | 0.007 | 0.005 | 0.262 | 0.049 | >0.5: Active <0.5: Non-active |
| H-HT (Human Hepatotoxicity) | 0.98 | 0.959 | 0.991 | 0.999 | 0.158 | >0.5: HHT positive <0.5: HHT negative | |
| DILI | 0.918 | 0.991 | 0.979 | 0.989 | 0.076 | >0.5 high risk, <0.5 no risk | |
| FDAMDD | 0.888 | 0.014 | 0.337 | 0.973 | 0.039 | +ve value FDAMDD (+), -ve value FDAMDD (-) | |
| Carcinogenicity | 0.154 | 0.84 | 0.256 | 0.435 | 0.751 | >0.5 carcinogens; <0.5 non-carcinogens | |
| Respiratory toxicity | 0.151 | 0.018 | 0.947 | 0.639 | 0.792 | >0.5: toxicants; <0.5: nontoxicants | |
| Acute toxicity rule | 0 alerts | 0 alerts | 0 alerts | 0 alerts | 0 alerts | 20 substructures | |
| Genotoxic carcinogenicity rule | 0 alerts | 0 alerts | 1alerts (A) | 0 alerts | 2 alerts (F$G) | 117 substructures | |
| Non-genotoxic carcinogenicity rule | 0 alerts | 0 alerts | 0 alerts | 1 alerts (C) | 0 alerts | 23 substructures | |
| SureChEMBL Rule | 0 alerts | 0 alerts | 1alerts (B) | 1 alerts (D) | 0 alerts | 164 substructures | |
| AMES (Ames mutagenicity) | 0.046 | 0.038 | 0.891 | 0.424 | 0.093 | >0.5: Positive <0.5: Negative |
|
DTG = Dolutegravir, LVD = Lamivudine, TDF = Tenofovir-disoproxil fumarate, LCP = Lenacapavir, HGG = Harpagide 5-O-β-D-glucopyranoside, DILI = Drug Induced Liver Injury, FDAMDD = FDA Maximum Recommended Daily Dose, hERG = Ppg = P-glycoprotein, MDCK = Madin-Darby canine kidney human cell-line, VD = Distribution volume, Fu = Fraction unbound, CL = Clearance, H-HT = Human Hepatotoxicity.